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CHARACTERISTICS OF THE STUDY GROUP AND DYNAMICS OF
PATHOGENETIC MARKERS ON THE BACKGROUND OF DIFFERENT ANTI-
COAGULATION MODES
Yakubov N. I.,Madumarova Z. Sh.
Department of Medical Radiology
Kodirova F. B.
1st year student of therapeutic faculty
Abstract:
Statins are a potential means of preventing venous thromboembolism (VTE),
complementing traditional
anticoagulants,
without
concomitant
bleeding-related
complications. The purpose of this study was to compare the prothrombotic activity of
different classes of lipid-lowering drugs in an active comparative study and determine
whether there is a link between the use of statins, fibrates/niacin and procoagulant
factors.Currently, taking statins is associated with lower plasma FXA levels than taking
fibrates/niacin. The effect on blood clotting factors may partly explain the benefits of statin
therapy in the primary and secondary prevention of VTE.
Keywords:
Study group characteristics, Pathogenetic markers, Anticoagulation therapy,
Anticoagulation modes, Coagulation parameters, Hemostasis markers, Thrombotic risk.
Introduction.
It is estimated that the incidence of venous thromboembolism (VTE) is
1-2 cases per 1000 person-years among people of European descent [1]. Inhibitors of 3-
hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the so-called statins, are a
class of lipid-lowering drugs that are widely used to prevent atherosclerosis [2]. There is
increasing evidence that statins are a promising means of preventing VTE, complementing
anticoagulants without concomitant bleeding-related complications [3,4,5,6,7,8,9]. In
addition to lowering lipid levels, statins have anti-inflammatory and antioxidant properties
[10, 11].
Moreover, mainly in the course of in vitro studies and observations, it was found that
they can have a positive effect on the walls of blood vessels and have antithrombotic
properties [12, 13]. These include decreased expression of tissue factor and thrombin
production, impaired thrombin-catalyzed procoagulant reactions, including fibrinogen
cleavage and activation of factors (F) V and FXIII, decreased activity of FVII and FVIII,
increased expression of endothelial thrombomodulin and increased fibrinolytic activity,
manifested in decreased expression of plasminogen activator inhibitor (PAI)-1 and increased
expression of tissue plasminogen activator (tPA) [14, 15]. In addition, it is assumed that it has
an antiplatelet effect, immediately and delayed inhibiting platelet activation, adhesion, and
aggregation, although previous research could not confirm these results in vitro [15, 16].
A recent randomized trial showed that 1 month of treatment with rosuvastatin at a
dosage of 20 mg/day leads to an improvement in coagulation parameters, primarily to a
decrease in factor VIII levels, in patients with previous DVT compared with those who did
not take statins [17]. Given that the effect of drugs is not necessarily common to all
representatives of the class, the reduction of procoagulant factors under the influence of
rosuvastatin may not apply to other statins currently on the market. It is known that different
types of statins reduce the level of low-density lipoproteins in different ways, reduce the
manifestations of atherosclerosis and inflammation. The lowest effect is observed in those
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taking pravastatin, followed by those taking simvastatin and atorvastatin, and the greatest in
those taking rosuvastatin [16, 18, 19].
A meta-analysis of randomized clinical trials has shown that there is a dose-effect
relationship in which rosuvastatin, which is most effective in stopping or slowing the
development of atherosclerosis, dyslipidemia, and inflammation, also provides the most
significant reduction in the risk of venous thrombosis [20]. We sought to find out whether
there is a relationship between statin use and indicators of procoagulant factors in participants
of the Dutch Obesity Epidemiology Study (NEO) [20].
Materials and methods.
We conducted a cross-sectional analysis of the baseline
indicators of the NEO study participants who took lipid-lowering drugs (statins or
fibrates/niacin) and compared their prothrombotic activity in an active comparative study.
The NEO study is a cohort study involving 6,671 people aged 45-65 years living in Leiden
(in the west of the Netherlands). Most of the participants had a div mass index (BMI) of 27
kg/m2 or higher. During the initial examination after a night of fasting, blood samples were
taken from participants in test tubes containing 0.106 M sodium citrate (Sarstedt, Numbrecht,
Germany). Plasma was obtained by centrifugation at 2500 × g for 10 minutes at room
temperature and stored in aliquots at -80 °C until analysis. Fibrinogen activity was measured
using the Claus method. In addition, activity FVIII:C, FIX:C, FXI:C was measured by
mechanical clot detection on an ACL TOP 700 analyzer (Werfen, Barcelona, Spain). All the
analyses were performed by laboratory technicians who were unaware of the status of the
samples.
Statistical analysis.
The general characteristics of the participants were presented in
the form of averages (± standard deviation) or figures (with percentages). Since
niacin/fibrates do not have antithrombotic properties [23], participants taking drugs of this
class were considered as a control group. The average values of blood clotting factors in
participants taking any statins were compared with the control group using linear regression
and presented as an average difference. The magnitude of the effect was shown with 95%
confidence intervals (CI). One assumption is that there is no preference in prescribing a lipid-
lowering drug to a particular patient and that clinical characteristics should be evenly
distributed among participants. Considering that this assumption may be too bold, we
included age, gender, smoking, BMI, hypertension, diabetes and common cardiovascular
diseases (myocardial infarction, angina pectoris, congestive heart failure) as potential
distorting factors in the regression analysis. All statistical analyses were performed in SPSS
version 22.0.
Results.
The general characteristics of the participants (n = 1043) who took drugs to
reduce lipid levels at the initial stage are shown in Table 1. Most of them took five different
classes of statins. A small subgroup (n = 22) took niacin/fibrates as drugs to reduce lipid
levels. More than two thirds of the participants reported that they had smoked (in the past or
currently), and almost half of them suffered from hypertension (systolic blood pressure (BP)
≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg). Approximately one third of the
patients suffered from diabetes (according to their own words, they had diabetes mellitus,
which they treated, or fasting plasma glucose > 7 mmol/l) or impaired glucose tolerance (6.1–
7 mmol/l).
The overall analysis showed that all blood clotting factors were lower in those taking
statins than in those taking fibrates/niacin, with the exception of fibrinogen, which was higher
in the groups taking statins (Table 2). The difference was most noticeable in FXI:C, which
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showed almost 17 IU/dl lower levels in patients taking statins than in patients taking
fibrate/niacin (mean difference was 17.1 IU/dl, 95% CI -30.0 to -4.3). Adjusting for potential
distorting factors did not change the results (the average difference was 18.3 IU/dl, 95% CI −
27.3--9.4). In addition, those who are currently taking statins have lower levels of FIX and
FVIII (adjusted mean difference − 11.3 IU/dl, 95% CI − 23.2 to 0.4) and − 15.8 IU/dl, 95%
CI − 31.6 to 0.003, respectively) with borderline statistical significance. Those taking
rosuvastatin have lower levels of FVIII and FIX than those taking other types of statins,
although these tests are hampered by a small number of participants.
Discussion.
We found that those who are currently taking statins have a level of
FXI:Plasma C is lower than that of those taking fibrates/niacin. The results of our study
confirm the conclusions of the STAtins Reduce Thrombophilia (START) study, according to
which a one-month course of treatment with rosuvastatin at a dose of 20 mg per day in
patients with previous VTE reduced the level of coagulation factors VII:C, FVIII:C, FXI:C
and the von Willebrand factor (vWF):Ag in plasma compared to those who did not take
statins [17]. We also showed that those who are currently taking statins have an FXI level.:C
is 18.3 IU/dl (from 9.4 to 27.3) lower, and the level of FVIII:C is 15.8 IU/dl (-0.003 to 31.6)
lower than that of those taking fibrates/niacin as lipid lowering drugs. The observed
difference appears to be more related to the use of rosuvastatin than other types of statins, as
they consistently had lower levels of FVIII:C and FXI:C is almost 18 IU/dl and about 15
IU/dl lower than in those who did not take statins. The effect of statins on the level of blood
clotting factors has previously been noted in various studies. In the Multi-Ethnic Study of
Atherosclerosis (MESA) cohort, consisting of people who did not suffer from cardiovascular
diseases or active cancer, those who took statins had lower levels of D-dimer and FVIII than
those who did not take statins [14]. Simvastatin treatment of patients with impaired glucose
tolerance and hypercholesterolemia decreased the levels of fibrinogen, FX:C, vWF:Ag, PAI-
1 and FVII activity in plasma. This also led to an increase in prothrombin time and activated
partial thromboplastin time. The simultaneous use of ezetimibe with simvastatin had a
synergistic effect on blood clotting parameters. In addition, ezetimibe has been reported to
enhance and stabilize the anticoagulant effect of warfarin, especially when combined with
statins [26]. Similarly, rosuvastatin, but not pitavastatin, increased the international
normalized value (INR) in healthy volunteers taking warfarin.
A Dutch study evaluating the short- and long-term effects of new statins on the
dosage of vitamin K antagonists (AVCS) has shown that patients taking statins require lower
doses of AVCS to achieve their INR target. The most significant effect was observed when
taking simvastatin and rosuvastatin. It was also noted that pravastatin enhances the
anticoagulant effect of dalteparin. On the other hand, the simultaneous use of rosuvastatin
and warfarin in a small number of healthy people did not affect the pharmacodynamics of
warfarin in a stable state. It has also been reported that rosuvastatin did not inhibit
thromboxane-dependent platelet aggregation in patients with a history of VTE.
Moreover, a one-year course of treatment with atorvastatin or simvastatin in patients
with coronary heart disease did not significantly affect the measured coagulation parameters,
although the fibrinolytic profile improved in patients taking these drugs. There are also
reports that statins do not affect the level or activity of FVII and FVIII. Although the
differences in coagulation rates observed in our research group, in particular FVIII and FIX,
between those who took statins and those who took fibrates/niacin, seemed to be more related
to rosuvastatin, we were unable to identify differences between rosuvastatin and other types
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of statins, probably due to- due to the small number of participants. It is believed that the side
effects of drugs are not necessarily common to all drugs, especially if the main mechanism of
action of the drug and the mechanism of side effects differ.
Thus, there is reason to believe that the antithrombotic properties of statins may be
inherent only to some of them. In most observational studies and randomized controlled trials,
it was concluded that the use of rosuvastatin was associated with the most significant (almost
40%) reduction in the risk of VTE compared with those who did not take statins. Moreover,
in the Dutch cohort of patients with a history of pulmonary embolism (PE), potent statins
with a lipid-lowering effect (for example, rosuvastatin) had the most significant effect in
preventing recurrence of PE (hazard ratio (HR) 0.29, 95% CI 0.07-1.16), followed by statins
of moderate efficacy (e.g., atorvastatin; HR 0.44, 95% CI 0.3–0.65) and low efficacy (e.g.,
pravastatin; HR 0.88, 95% CI 0.5–1.54) [43]. Despite these results, several reports emphasize
the lack of association between the type of statins and the risk of first or repeated VTE.
Finally, we showed that, unlike other coagulation factors measured, fibrinogen levels in those
who took statins were higher than those who took fibrates/niacin, although the difference was
statistically insignificant. Since fibrinogen is associated with pro-inflammatory and
procoagulant effects, statins could be expected to reduce fibrinogen levels. A previous study
reported that fibrinogen levels decreased after 12 weeks of treatment with simvastatin at a
dosage of 20 mg per day in patients with impaired fasting glucose levels and
hypercholesterolemia.
Conclusion.
Currently, taking statins is associated with lower levels of FXA in blood
plasma. The type of statin taken may make a difference, although further randomized
controlled trials with a much larger number of participants are needed.
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